Nat Rev Dis Primers. Paules C, Subbarao K. Influenza vaccine effectiveness among high-risk groups: a systematic literature review and meta-analysis of case-control and cohort studies. Hum Vaccin Immunother. Buckland BC. The development and manufacture of influenza vaccines. The pathway to a universal influenza vaccine. Khurana S. Development and regulation of novel influenza virus vaccines: a United States young scientist perspective.
Neuraminidase inhibitors: who, when, where? Clin Microbiol Infect. Sugaya N. Widespread use of neuraminidase inhibitors in Japan. J Infect Chemother. WHO Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med. McKimm-Breschkin JL. Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza Other Respir Viruses. Single-dose inhaled laninamivir: registered in Japan and its potential role in control of influenza epidemics.
Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Impact of outpatient neuraminidase inhibitor treatment in patients infected with influenza A H1N1 pdm09 at high risk of hospitalization: an individual participant data metaanalysis.
Clin Infect Dis.
Clinical implications of antiviral resistance in influenza. Kamali A, Holodniy M. Influenza treatment and prophylaxis with neuraminidase inhibitors: a review. Infect Drug Resist. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, Antiviral Res. Community transmission of oseltamivir-resistant A H1N1 pdm09 influenza. Generation and characterization of influenza A viruses with altered polymerase fidelity. Nat Commun. Experimental treatment with favipiravir for ebola virus disease the JIKI Trial : a historically controlled, single-arm proof-of-concept trial in Guinea.
PLoS Med. Prevention and treatment of respiratory viral infections: presentations on antivirals, traditional therapies and host-directed interventions at the 5th ISIRV Antiviral Group conference. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit.
Baloxavir marboxil for uncomplicated influenza in adults and adolescents. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci Rep. Serological evidence for prevention of influenzal infection in volunteers by an anti-influenzal drug adamantanamine hydrochloride. Antimicrob Agents Chemother. PubMed Abstract Google Scholar. Treatment of influenza. The therapeutic efficacy of rimantadine HC1 in a naturally occurring influenza A2 outbreak. Am J Med Sci. Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors.
J Med Chem. Rational design of potent sialidase-based inhibitors of influenza virus replication. BCX RWJ : discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. CS, a prodrug of the new neuraminidase inhibitor R, shows long-acting anti-influenza virus activity. In vitro and in vivo activities of anti-influenza virus compound T Strittmatter SM. Overcoming drug development bottlenecks with repurposing: old drugs learn new tricks.
Nat Med. Drug Innovation. Novel Drug Approvals for PubMed Abstract. Chart Pack: Biopharmaceuticals in Perspective, Summer Phrma Drug repositioning: identifying and developing new uses for existing drugs.
Combating the Threat of Pandemic Influenza Drug Discovery Approaches
Nat Rev Drug Discov. Drug repurposing: progress, challenges and recommendations. Devillers J. Repurposing drugs for use against Zika virus infection. Giving drugs a second chance: overcoming regulatory and financial hurdles in repurposing approved drugs as cancer therapeutics. Front Oncol. The rise, fall and subsequent triumph of thalidomide: lessons learned in drug development. Ther Adv Hematol. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond.
Abelson kinase inhibitors are potent inhibitors of severe acute respiratory syndrome coronavirus and middle east respiratory syndrome coronavirus fusion. J Virol. Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. Drug discovery: predicting promiscuity. Reddy AS, Zhang S. Polypharmacology: drug discovery for the future. Expert Rev Clin Pharmacol. Shifting from the single- to the multitarget paradigm in drug discovery. Drug Discov Today.
Chapter 12 - drug repurposing for epigenetic targets guided by computational methods. In: Epi-Informatics , ed J. Medina-Franco Boston: Academic Press , — CrossRef Full Text. Opportunities and challenges in phenotypic drug discovery: an industry perspective. Swinney DC, Anthony J. How were new medicines discovered? Drug repositioning: playing dirty to kill pain.
CNS Drugs. How academic labs can approach the drug discovery process as a way to synergize with big pharma. Trends Microbiol. Applications of chemogenomic library screening in drug discovery. DrugBank 3. Nucleic Acids Res. In silico prediction of novel therapeutic targets using gene—disease association data. J Transl Med. Computational drug repositioning: from data to therapeutics.
Clin Pharmacol Ther. In silico pharmacology for drug discovery: methods for virtual ligand screening and profiling. Br J Pharmacol. Systematic drug repurposing through text mining. Methods Mol Biol. Identification of drug candidates and repurposing opportunities through compound-target interaction networks. Expert Opin Drug Discov. Network-based drug discovery: coupling network pharmacology with phenotypic screening for neuronal excitability. J Mol Biol.
Associating drugs, targets and clinical outcomes into an integrated network affords a new platform for computer-aided drug repurposing. Mol Inform. Systematic evaluation of drug-disease relationships to identify leads for novel drug uses. A novel two-stage, transdisciplinary study identifies digoxin as a possible drug for prostate cancer treatment. Cancer Discov.
Allarakhia M. Open-source approaches for the repurposing of existing or failed candidate drugs: learning from and applying the lessons across diseases. Drug Des Devel Ther. Systems pharmacology: bridging systems biology and pharmacokinetics-pharmacodynamics PKPD in drug discovery and development. Pharm Res. Systems pharmacology in small molecular drug discovery. Int J Mol Sci. Drug repurposing for viral infectious diseases: how far are we? Akpovwa H. Chloroquine could be used for the treatment of filoviral infections and other viral infections that emerge or emerged from viruses requiring an acidic pH for infectivity.
Cell Biochem Funct. Al-Bari MAA. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol Res Perspect. Clinical regimens of favipiravir inhibit zika virus replication in the hollow-fiber infection model. Ludwig S. Will omics help to cure the flu?
Repurposing kinase inhibitors as antiviral agents to control influenza a virus replication. Assay Drug Dev Technol. Fedson DS. Treating influenza with statins and other immunomodulatory agents. Clinician-initiated research on treating the host response to pandemic influenza. Mechanisms of action and efficacy of statins against influenza. Biomed Res Int. Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J Biol Chem. The susceptibility of circulating human influenza viruses to tizoxanide, the active metabolite of nitazoxanide.
Peroxisome proliferator-activated receptor and AMP-activated protein kinase agonists protect against lethal influenza virus challenge in mice. Increased survival after gemfibrozil treatment of severe mouse influenza. Front Microbiol. Targeting intracellular signaling as an antiviral strategy: aerosolized LASAG for the treatment of influenza in hospitalized patients. Emerg Microbes Infect. Davidson S. Treating influenza infection, from now and into the future. Front Immunol. Inhibition of the inflammatory cytokine tumor necrosis factor-alpha with etanercept provides protection against lethal H1N1 influenza infection in mice.
Crit Care. Obatoclax, saliphenylhalamide, and gemcitabine inhibit influenza a virus infection. Discovery of dapivirine, a nonnucleoside HIV-1 reverse transcriptase inhibitor, as a broad-spectrum antiviral against both influenza A and B viruses. The clinically approved MEK inhibitor Trametinib efficiently blocks influenza A virus propagation and cytokine expression.
Rohini K, Shanthi V. Hyphenated 3D-QSAR statistical model-drug repurposing analysis for the identification of potent neuraminidase inhibitor. Cell Biochem Biophys. Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of influenza A virus. Drug repurposing identifies inhibitors of oseltamivir-resistant influenza viruses. Angew Chem Int Ed Engl. Influenza virus-host interactome screen as a platform for antiviral drug development.
Cell Host Microbe. Gene expression signature-based screening identifies new broadly effective influenza a antivirals. Repurposing of drugs as novel influenza inhibitors from clinical gene expression infection signatures. Future Virol. HTS antiviral screening algorithm. One advantage of a cell based assay is that it can identify compounds that are effective against known and unknown targets, as well as identify compounds that are metabolized by the cell into effective antivirals.
Disadvantages include an inability to recognize effective but toxic compounds, compounds that are excluded from passage through the cellular membrane, or compounds that inhibit through aggregation-based mechanisms. The growing use of cell-based assays is balanced by the technical challenges in developing robust, large-scale systems—that is, the laborintensive production of large quantities of cells and the inherent assay variability due to differences in cell passage number and handling.
CPE induced by viral infection is a well-documented and frequently exploited determinant for viral propagation in lytic viruses, but one which requires a reliable method for determining viability. A variation of this assay that could be adapted to screen large libraries has been demonstrated more recently using CV-1 cells that have been infected with a high titer of SV40 virus containing the M2 cDNA sequence.
This assay format is suitable for miniaturization, as well as for automation of liquid handling and reading, and is fully adaptable to HTS as both a primary or secondary assay. Biochemical HTS Assays. For HTS primary antiviral screening, biochemical assays can often be performed in a fraction of the time hours instead of days that a cell-based assay can, and they are not bound by compound toxicity issues, making them ideal for targeted primary HTS. An effective and sensitive NA assay that directly measures sialidase activity instead of indirectly by enzyme cascade, as detailed in Ref.
After a minute incubation to allow for the compounds to potentially bind to the NA on the surface of the virus, the substrate is diluted in reaction buffer and added to the plates, allowed a minute reaction time, and stopped by addition of a high-pH stop buffer. This method has recently succeeded in identifying novel NA inhibitors.
The HA protein is instrumental during the initial stages of infection, and therefore a cell-based primary HTS assay would serve to screen compounds for the target activities that are associated with HA—that is, the surface glycoprotein sialic acid recognition, membrane fusion that is mediated by the HA2 fusion peptide, and activation by protease cleavage of HA0.
The lack of HA-associated catalytic activity makes HTS assay development a challenge that depends heavily on the chosen target and method of endpoint. This method might be adapted to target small molecules that inhibit membrane fusion of the HA2 peptide, thereby rapidly surveying and identifying effective small molecule combinations from large compound libraries. These assays have utilized UV-crosslinking to capture RNA-protein binding and electrophoretic detection to examine the reaction products.
This assay has been adapted to a well microplate format, and the addition of automated robotics would allow several thousand compounds to be screened by scintillation counting in a single day.
The protein- and RNA-binding potential of NS1 is an elusive activity to target for inhibition by small molecules, although inhibition by both RNA aptamers and short peptides has been proposed. However, these assays have not been developed or validated for HTS at this time. Assay throughput will certainly be reduced at high biosafety in favor of increased safety. Kiselar, J. Biochemistry , 38, — Thompson, W. Szucs, T. B, 11— Meltzer, M. Phipps, L. Methods , , — United States Department of Agriculture. Vahlenkamp, T. Olsen, B. Layne, S. Hao, W. Development of a novel dicistronic reporter-selectable hepatitis C virus replicon suitable for high-throughput inhibitor screening.
Kleymann, G. A generally applicable, high-throughput screening-compatible assay to identify, evaluate, and optimize antimicrobial agents for drug therapy. Steinhauer, D. Hampson, A. Stevens, J. Nayak, D. Noah, D. Bruns, K. Lee, M. Nucleic Acids Res. Spector, R. The heart of drug discovery and development: rational target selection. Pharmacology , 77, 85— Cattoli, G. Basel , , 99— Wiley, D.
Huang, Q. Acta , , 3— Park, H. Leash in the groove mechanism of membrane fusion. Kido, H. Isolation and characterization of a novel trypsin-like protease found in rat bronchiolar epithelial Clara cells. A possible activator of the viral fusion glycoprotein. Cross, K. EMBO J. Methods , , 9— Fornabaio, M. Simple, intuitive calculations of free energy of binding for protein— ligand complexes. Computational titration and pH effects in molecular models of neuraminidase-inhibitor complexes.
J Med. Mungall, B. Avian Dis. Science , , — Gupta, R. Pinto, L. Viral ion channels as models for ion transport and targets for antiviral drug action. FEBS Lett. Ozaki, T. Viral Immunol. Saldanha, S. Assay principle for modulators of protein—protein interactions and its application to non-ATP-competitive ligands targeting protein kinase A. Jeon, S. Boulo, S. Hooker, L. Biochemistry , 42, — Fechter, P. Recognition of mRNA cap structures by viral and cellular proteins. De Gregorio, E. RNA , 4, — Hutchinson, K.
Sin Nombre virus mRNA synthesis. Virology , , — Eriksson, B. Portela, A. Elton, D. Area, E. Rowe, T. Shu, L. Diagnostic approach for differentiating infected from vaccinated poultry on the basis 68 Davey, J. Min, J. Li, S. Virology , , 13— Li, Z. Qian, X. RNA , 1, — Neumann, G. USA , 96, — Donelan, N. Krug, R. Henklein, P. Chen, W. Yamada, H. Noah, J. Zhang, J. Zhang, A. Starick, E. Public Health , 53, — Bai, G. Woolcock, P. Crossley, B. Dawson, E. Townsend, M. World Health Organization. Qiao, C. Treanor, J. Bateman, J.
Auewarakul, P. Vaccine Stephenson, I. Unpublished data. Reynolds, M. BMC Public Health , 6, Choi, K. Monoclonal antibody-based competitive enzyme-linked immunosorbent assay for detecting and quantifying West Nile virus-neutralizing antibodies in horse sera. Vaccine Immunol. Gupta, C. Biologicals , 24, 41— Zhou, G.
Ferrer, M. Fox, S. Highthroughput screening: update on practices and success. Westby, M. Cell-based and biochemical screening approaches for the discovery of novel HIV-1 inhibitors. Shoichet, B.
- Sloppy Seconds: The Tucker Max Leftovers;
- Image and Video Compression for Multimedia Engineering. Fundamentals, Algorithms and Standards.
- Introduction to bioinformatics.
- Theory and Evaluation of Single-Molecule Signals.
Screening in a spirit haunted world. Today , 11, — Severson, W. Digan, M. McCoy, M. Methods , , 71— Mould, J. Amplex Red neuraminidase Sialidase Assay.
Treatment of Influenza: Prospects of Post-Transcriptional Gene Silencing Through Synthetic siRNAs
Molecular Probes , A, 1—3. Blick, T. Varghese, J. Liu, A. China C. Life Sci. Szecsi, J. Targeted retroviral vectors displaying a cleavage site-engineered hemagglutinin HA through HA-protease interactions. Brownlee, G. Bhat, J. Wang, Y. Chien, C. Biochemistry , 43, — Prevention, C. Ghosh, R. It can be divided into three types, A, B, and C, of which A is the primary pathogen for humans. Upon binding to the cell surface receptor, the virus enters by endocytosis. Once in the endosome, low pH mediates the fusion of the viral and endosome membranes so that the viral nucleocapsids are released into the cytoplasm and then imported into the cell nucleus.
After translation in the cytoplasm, the viral proteins are then transported back to the nucleus to initiate replication of the genome and secondary mRNA transcription. Subsequently, viral ribonucleoprotein complexes are assembled in the nucleus and then transported to the plasma membrane where budding of mature virions occurs. Type I interferon is immediately induced upon viral infection and subsequently leads to the induction of hundreds of genes that collectively create an antiviral state in the cell.
It resides in the perinuclear region and is believed to inhibit nuclear import and cell-cycle progression. It exists at low levels in most cell types and is potently induced by IFN. NS1 is a NS1 mediates this by binding a purinecontaining bulge in a stem structure of the splicesomal U6 small nuclear RNA. Therefore, inhibition of total cellular gene expression would also inhibit ISG induction. This may suggest that conducting similar experiments in other strains of mice may provide more insight into other potential mediators of host defense.
Although some PKR protein is nuclear, it is predominantly detected in the cytoplasm, and therefore nuclear sequestration of dsRNA could effectively prevent it from activating PKR. It contains nine tandemly arranged tetratricopeptide repeats TPR as well as a J-domain that shares homology with the DnaJ heat shock family of proteins.
Hsp40 inhibition of PKR may involve a third component, Hsp Preliminary results have been noted in a review by Kash et al. PERK is activated by the build-up of misfolded proteins in the endoplasmic reticulum, which is known to induce the unfolded protein response UPR. Despite the overlap, ISG15 and dsRNA can bind simultaneously and the binding of one has no appreciable effect on the other. The OAS and RNase L proteins function in tandem as a sensor and effector mechanism, respectively, that ultimately leads to the cleavage of both cellular and viral RNAs to inhibit virus replication.
OAS is activated by viral dsRNA, typically produced during viral genome replication or the transcription of viral genes. This analysis showed no inhibition by the mutated virus and concluded that dsRNA binding was not involved in the suppression of IFN. The R38A mutation used in both studies is located in the common NLS and therefore may differentially affect subcellular localization of the two mutant NS1 proteins.
IFN, in combination with the nucleoside analogue ribavirin, is currently the primary therapeutic regimen for hepatitis C virus. Likewise, targeting the NS1 protein directly could also be a key strategy. Russell, C. Cell , , — Lamb, R. Orthomyxoviridae: The viruses and their replication. Ronni, T. Plotch, S. Cell , 23, — USA , 76, — Fortes, P. Park, Y. Hinshaw, V. Ikeda, H. The critical role of type-1 innate and acquired immunity in tumor immunotherapy. Cancer Sci. Stark, G.
How cells respond to interferons. Andrejeva, J. Yoneyama, M. Hornung, V. Kato, H. Pichlmair, A. Meylan, E. Kawai, T. Fitzgerald, K. Sharma, S. Triggering the interferon antiviral response through an IKK-related pathway. Xu, L. Cell , 19, — Seth, R. Lin, R. Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation.
Alexopoulou, L. Guillot, L. Lund, J. Recognition of single-stranded RNA viruses by Toll-like receptor 7.
Perry, A. The host type I interferon response to viral and bacterial infections. Cell Res. Cell , Suppl. Der, S. USA , 95, — Hefti, H. Staeheli, P. Cell , 44, — Haller, O. Aebi, M. Pavlovic, J. Jin, H. Zurcher, T. Frese, M. Human MxA protein inhibits tick-borne Thogoto virus but not Dhori virus. Schnorr, J. MxA-dependent inhibition of measles virus glycoprotein synthesis in a stably transfected human monocytic cell line.
Landis, H. Kochs, G. King, M. Inhibition of nuclear import and cell-cycle progression by mutated forms of the dynamin-like GTPase MxB. Patel, R. Characterization of the interactions between double-stranded RNA and the double-stranded RNA binding domain of the interferon induced protein kinase. Cell Mol. Bevilacqua, P. Biochemistry , 37, — Clemens, M.
Interferon Cytokine Res. Levin, D. Regulation of protein synthesis: Activation by double-stranded RNA of a protein kinase that phosphorylates eukaryotic initiation factor 2. USA , 75, — Galabru, J. Autophosphorylation of the protein kinase dependent on double-stranded RNA. Kimball, S. Regulation of translation initiation by amino acids in eukaryotic cells. Panniers, R. Perkins, D. Chu, W. Immunity , 11, — Saunders, L. Balachandran, S. Kumar, A. Yang, Y. Unique functions of the NS1 protein.
Yoshida, T. Virology , , 87— Shapiro, G. Bornholdt, Z. Qiu, Y. Lu, Y. Enami, K. Burgui, I. Bergmann, M. Garcia-Sastre, A. RNA , 5, — Tan, S. Hatada, E. Ramana, C. Regulation of c-myc expression by IFN-gamma through Stat1-dependent and -independent pathways. Jagus, R. PKR, apoptosis and cancer. Ito, T. Liu, J. Virology , , 41— Dauber, B. Kash, J. Tang, N. The kDa cellular inhibitor of the double stranded RNA-dependent protein kinase requires the tetratricopeptide repeat 6 and DnaJ motifs to stimulate protein synthesis in vivo.
Katze, M. Lee, T. The 58,dalton cellular inhibitor of the interferon-induced double-stranded RNAactivated protein kinase PKR is a member of the tetratricopeptide repeat family of proteins. Gale, M. Biochemistry , 41, — Melville, M. USA , 94, 97— Bilgin, D. Cell , 4, — Fels, D. Cancer Biol. Oyadomari, S. Cotranslocational degradation protects the stressed endoplasmic reticulum from protein overload. Harding, H. Cell , 7, — Endoplasmic reticulum stress and the development of diabetes: A review.
Diabetes , 51 Suppl. Ladiges, W. Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes , 54, — Yuan, W. Loeb, K. The interferon-inducible kDa ubiquitin homolog conjugates to intracellular proteins. Zou, W. Wong, J. Zhao, C. Dastur, A.
Takeuchi, T. Tokyo , , — Knobeloch, K. Lenschow, D. Okumura, A. Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Player, M. Samuel, C. Antiviral actions of interferons. Silverman, R. Implications for RNase L in prostate cancer biology. Tanaka, N. Zhou, A. Cell , 72, — Dong, B. Intrinsic molecular activities of the interferon-induced A-dependent RNase.
De Benedetti, A. USA , 84, — Hassel, B. A dominant negative mutant of A-dependent RNase suppresses antiproliferative and antiviral effects of interferon. Meurs, E. Interferon-mediated antiviral state in human MRC5 cells in the absence of detectable levels of A synthetase and protein kinase. Taylor, J. Baskin, C. Wang, X. Fernandez-Sesma, A. Talon, J. Greenspan, D. Kang, D. Guo, Z. Mibayashi, M.
B Biol. Some properties of interferon. Baron, S. Sperber, S. Matthews, S. Peginterferon alfa-2a: A review of approved and investigational uses. Akira, S. TLR signaling. Amlie-Lefond, C. Innate immunity for biodefense: A strategy whose time has come. Allergy Clin. Ichikawa, T. Geranylgeranylacetone induces antiviral gene expression in human hepatoma cells. Unoshima, M.
Seo, S. Most of those agents belong to the families orthomyxoviridae, paramyxoviridae, picornaviridae, coronaviridae, adenoviridae, and so on. Among them, the orthomyxoviruses and paramyxoviruses share a common nature, that is, they have negative-strand RNA and have viral envelopes with a plasma membrane structure, and they are similar in several steps of viral replication. In Table 4. Most human viral respiratory infections are highly contagious and sometimes epidemic. Dead cells are unable to reduce MTT to formazan. In addition, colorimetric assays facilitate the mass screening of compounds and computerization of the obtained data.
We found that the critical points for the sensitive colorimetric method are as follows: First, the cells have to be used in a suspended state; second, cells, virus, and diluted compounds have to be introduced simultaneously to the culture plate; and third, the plate has to be centrifuged at g for 10 min before incubation. As shown in Table 4. TABLE 4. Figure 4.
Thus, both the LDH and MTT methods were proven to be applicable for the titration and evaluation of the antiviral activity of compounds for these viruses. The use of suspended cells and centrifugation at low speed were requisites for the colorimetric antiviral assay of myxoviruses. Among these, pyrazofurin, 3-deazaguanine, and ribavirin emerged as selective antiRSV agents Fig. Chemical structures of the nucleoside analogues that have anti-myxovirus activity. Pyrazofurin and 3-deazaguanine inhibited virus growth in HEp-2 cells at 0. Ribavirin has been approved for the clinical treatment of RSV infection as aerosol inhalation.
Thus pyrazofurin and 3-deazaguanine appeared to be candidate anti-RSV agents in addition to ribavirin. This report indicates that pyrazofurin was more toxic for chick embryos than ribavirin. Untreated Treated with Pyrazofurina,b 1 2 3 4 5 Average There was no obvious toxicity for rats. Long A. FM A. NS B. Sendai Fushimi 2. CA Greer 3. Bangkok H1N1 A. Ishikawa H3N2 B. Their EC50s for paramyxovirus except for RSV in vitro were to fold less than that of ribavirin. Finally, mizoribin is a compound that has been applied clinically as an immunosuppressive drug.
Sulfated Polysaccharides Sulfated polysaccharides such as dextran sulfate have been reported to be potent and selective inhibitors of several envelope viruses. Hosoya et al. Although we were not able to analyze the sugar sequence of the polysaccharide, the composition of the sugar moiety was analyzed. The molar ratio of sugars in OKU is glucose 1. OKU and OKU are noncytotoxic substances whereas we were concerned about their anti-coagulating effect on normal plasma.
APTT, activated partial thromboplastin time. OKU and are nontoxic and broad-spectrum anti-myxovirus substances. Since these substances exist abundantly in nature and are easy to extract from microorganisms, it is worth of investigating them further to develop anti-myxovirus drugs from these substances. Polyoxometalates Polyoxometalates POM are soluble inorganic cluster-like compounds formed principally of an oxide anion and early transition metal cations such as tungsten W , molybdenium Mo , niobium Nb , antimony Sb , vanadium V , and so on.
HS inhibited both adsorption and the fusion process of RSV infection, whereas it only inhibited the fusion process of FLUV to the cellular membrane. Six compounds showed SIs of more than Among these compounds, PM, , , and were V-containing polyoxotungstates and PM, , were Ticontaining polyoxotungstates. Coronavirus is a positive-strand RNA virus and is covered with an envelope that is obtained at the release of the virus from the cell membrane.
Coronaviruses are infectious in a number of animals, namely, pigs, cattle, cats, birds, and so on. A coronavirus that infects humans causes a severe, sometimes mortal respiratory disease called SARS. Table 4. The abscissa indicates intensity of populations of infected cells and the ordinate indicates the number of cells. The rightmost line is a population of infected cells without compounds, and the leftmost line is that of uninfected cells.
See color insert. EC50 was determined by the plaque reduction method. For other viruses it was determined by the MTT method. PM and PM had Keggin sandwich structures. The SIs greater than 30 are indicated in boldface. PM, , and have particular structures—that is, Keggin dimmer, Lindqvist triangle, and Keggin triangle, respectively. Antisense sequences are underlined. R represents an alkyl loop hexa-ethylene glycol structure. For the delivery of antisense ODN, they used liposome encapsulation of the materials.
The former is designated RBI and the latter is commercialized as palivizumab. Both compounds interacted with the early adsorption and late stages probably fusion and penetration of virus replication. We also examined the antiRSV activity of both compounds in vivo, using intranasal infection of RSV to cotton rats or immunosuppressed mice by cyclophosphamide injection.
RD was administrated as an aerosol for 2 hours twice daily 1. Anti-RSV compounds. Top: NMSO3. Bottom: RD Fresh clinical strain. When the section of infected lung was observed histologically, the evidence of interstitial pneumonia observed in untreated animals i. However, I am still adhering to the broadspectrum anti-respiratory virus agents for the reasons cited above. Since ribavirn is a broad-spectrum anti-myxovirus compound, synergistic effects were mainly examined between ribavirin and the other compounds.
The effect of the combination of PM and ribavirin on FLUV replication was evaluated by median-effect principle and isobologram, and it was analyzed by using a microcomputer with dose—effect analysis software. When we examined the in vitro combination effects and calculated the CI in several ratios of combination of PM and ribavirin, the CI was consistently lower than 1. As shown in Fig. Combination of PM and ribavirin at a ratio of 1 : 16 —— and 1 : 4 were analyzed under mutually nonexclusive assumptions.
Figures 4. These compounds exceeded ribavirin in the potency and selectivity of their anti-myxovirus effects in vitro. Combination index with respect to the fraction affected by the inhibition of a measles virus multiplication in Vero cells and b mumps virus in Vero cells. Mice were infected with virus 1. The compounds were given to the infected mice every 12 hr for 4 days starting at 8 hr after viral inoculation.
The materials were injected 2 mm deep with a gauge needle at two hr intervals into the subarachnoid space of hamsters under ether anesthesia. The author thanks for the technical assistance of Dr. Klein, M. The impact of infection with human metapneumovirus and other respiratory viruses in young infants and children at high risk for severe pulmonary disease. Lamson, D. George, K.
Drug Discovery Approaches
Yokota, T. The rational drug design laboratories in Fukushima, Japan. Antiviral News , 4, 60— Watanabe, W. MTT colorimetric assay system for the screening of anti-orthomyxo- and paramyxoviral agents. Methods , 51, — Mori, S. A colorimetric LDH assay for the titration of infectivity and the evaluation of anti-viral activity against ortho- and paramyxoviruses. Tohoku J. Kawana, F. Inhibitory effects of antiviral compounds on respiratory syncytial virus replication in vitro. Shigeta, S. Hosoya, M.
Chemotherapy for acute respiratory viral infections. Shonika Rinsho , 41, — In Japanese. Shuto, S. New neplanocin analogues. Kosugi, Y. Antiviral activities of mizoribine and other inocine monophosphate dehydrogenase inhibitors against several ortho- and paramyxoviruses. Ito, M. Baba, M. USA , 85, — Differential inhibitory effects of sulfated polysaccharides and polymers on the replication of various myxoviruses and retroviruses, depending on the comparison of the target amino acid sequences of the viral envelope glycoproteins.
Hashimoto, K. Okutani, K. Isolation and characterization of a fucosamine containing polysaccharides from a marine strain of Psudomonas. Nippon Suisan Gakkaishi. Yamamoto, N. Ikeda, S. In vivo activity of a novel series of polyoxosilicotungstates against human myxo-, herpes, and retroviruses. Barnard, D. Potent inhibition of respiratory syncytial virus by polyoxometalates of several structural classes.
Huffman, J. Broad spectrum anti-RNA virus activities of titanium and vanadium substituted polyoxotungstates. AntiRNA virus activity of polyoxometalates. Hatta, T. Abe, T. Hamazaki, H. Acta , 85, — Mizuta, T. Antisense oligonucleotides directed against the Nature Biothechnol. Torrence, R. USA , 90, — Leaman, D. Cramer, H. Targeted therapy of respiratory syncytial virus by antisense. Nucleosides Nucleotides Nucleic Acid , 24, — Palivizmab, a humanized respiratory syncytial virus monoclonal antibody reduces hospitalization from respiratory syncytial virus infections in high risk infants.
Kimura, K. Antiviral activity of NMSO3 against respiratory syncytial virus infection in vitro and in vivo. Sudo, K. Douglas, J. Wyde, P.
Related Combating the Threat of Pandemic Influenza: Drug Discovery Approaches
Copyright 2019 - All Right Reserved